Enantioselective carbenoid insertion into C(sp(3))-H bonds.

The enantioselective carbenoid insertion into C(sp(3))-H bonds is an important tool for the synthesis of complex molecules due to the high control of enantioselectivity in the formation of stereogenic centers. This paper presents a brief review of the early issues, related mechanistic studies and recent applications on this chemistry area.

The relative roles of calcium, phosphorus, and parathyroid hormone in glucose- and tolbutamide-mediated insulin release.

The relative contributions of Ca++, phosphorus, and parathyroid hormone (PTH) on insulin secretion were evaluated in three groups of dogs. Dogs were studied with glucose infusions (group I) or standard intravenous glucose tolerance tests (IVGTT) (group II) before and after the development of diet-induced hypophosphatemia. Mean serum phosphorus levels for both groups fell from 4.1 to 1.1 mg/100 ml. Animals in group I demonstrated a fall in glucose disappearance rates (Kg) from 5.3+/-0.6% min to 3.5+/-0.5% after induction of hypophosphatemia (P less than 0.001). Mean insulin response was significantly greater in the hypophosphatemic animals than in controls in this group. In group II animals, mean insulin areas obtained during the IVGTT increased from 1,426+/-223 to 2,561+/-141 muU/ml/60 min after induction of hypophosphatemia, and were unaffected by Ca++ or PTH administration. Ca++ administration, but not hypophosphatemia or PTH infusion, increased significantly the mean insulin response to tolbutamide. Secondary hyperparathyroidism was induced by dietary manipulation in four dogs (group III). Mean PTH values increased from 71.4+/-2.1 to 3,012+/-372 pg/ml (P less than 0.001). Mean insulin response to an IVGTT was similar to group III animals, but increased from 1,352+/-128 to 1,894+/-360 muU/ml/60 min after the excessive dietary phosphorus was reduced for 3 mo, and plasma phosphorus fell from 3.2+/-0.1 to 2.8+/-0.3 mg/100 ml. PTH values decreased to 647+/-53 pg/ml. The insulin response to tolbutamide was comparable to that in group II animals, but increased significantly after calcium administration. Immunoreactive insulin disappearance rates were unaffected by hypophosphatemia or diet-induced secondary hyperparathyroidism. These data demonstrate that hypophosphatemia is associated with an augmented glucose-stimulated insulin release, without any effect on tolbutamide-stimulated insulin release. Hypercalcemia produces an augmented tolbutamide-stimulated insulin release with no apparent effect on glucose-stimulated insulin release. Finally, PTH does not appear to be an insulin antagonist and has no apparent effect on either glucose- or tolbutamide-stimulated insulin release in animals with dietary-induced secondary hyperparathyroidism.

The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man.

Sequential determinations of glucose outflow and inflow, and rates of gluconeogenesis from alanine, before, during and after insulin-induced hypoglycemia were obtained in relation to alterations in circulating epinephrine, norepinephrine, glucagon, cortisol, and growth hormone in six normal subjects. Insulin decreased the mean (+/-SEM) plasma glucose from 89+/-3 to 39+/-2 mg/dl 25 min after injection, but this decline ceased despite serum insulin levels of 153+/-22 mul/ml. Before insulin, glucose inflow and outflow were constant averaging 125.3+/-7.1 mg/kg per h. 15 min after insulin, mean glucose outflow increased threefold, but then decreased at 25 min, reaching a rate 15% less than the preinsulin rate. Glucose inflow decreased 80% 15 min after insulin, but increased at 25 min, reaching a maximum of twice the basal rate. Gluconeogenesis from alanine decreased 68% 15 min after insulin, but returned to preinsulin rates at 25 min, and remained constant for the next 25 min, after which it increased linearly. A fourfold increase in mean plasma epinephrine was found 20 min after insulin, with maximal levels 50 times basal. Plasma norepinephrine concentrations first increased significantly at 25 min after insulin, whereas significantly increased levels of cortisol and glucagon occurred at 30 min, and growth hormone at 40 min after insulin. Thus, insulin-induced hypoglycemia in man results from both a decrease in glucose production and an increase in glucose utilization. Accelerated glycogenolysis produced much of the initial, posthypoglycemic increment in glucose production. The contribution of glycogenolysis decreased with time, while that of gluconeogenesis from alanine increased. Of the hormones studied, only the increments in plasma catecholamines preceded or coincided with the measured increase in glucose production after hypoglycemia. It therefore seems probable that adrenergic mechanisms play a major role in the initiation of counter-regulatory responses to insulin-induced hypoglycemia in man.

The effect of hyperglucagonemia on blood glucose concentrations and on insulin requirements in insulin-requiring diabetes mellitus.

The effect of elevated glucagon concentrations on insulin requirements and on blood glucose concentrations was studied in five insulin-requiring diabetic subjects during feedback control of hyperglycemia with an automated glucose-controlled insulin infusion system (artificial endocrine pancreas) for six to eight hours. Two levels of hyperglucagonemia were induced by means of constant intravenous infusion. Raising plasma glucagon concentrations to levels reported in poorly controlled diabetics (450 to 665 pg. per milliliter) did not alter total insulin requirements or blood glucose concentrations. Higher glucagon concentrations (850 to 1,050 pg. per milliliter) caused a modest (26 per cent) increase in insulin requirements and only a slight increase in mean blood glucose concentrations. These studies demonstrate that the degree of hyperglucagonemia found most frequently in insulin-requiring diabetics does not increase insulin requirements or decrease insulin effectiveness in patients given insulin in amounts appropriate to maintain euglycemia.

Overnight basal insulin requirements in fasting insulin-dependent diabetics.

Overnight basal insulin requirements to maintain eugycemia were determined in six insulin-requiring diabetic subjects using a feedback-controlled (closed loop) insulin infusion system. Mean hourly insulin infusion rates, required to maintain plasma glucose concentrations at approximately 100 mg/dl, were remarkably stable from 2400 h to 0600 h; however, a twofold to threefold increase in insulin requirements was observed in each subject between 0600 h and 0900 h. This increase in amount of basal insulin required was not associated with increases in plasma glucagon or growth hormone concentrations, but occurred simultaneously with normal diurnal increases in plasma cortisol. These findings suggest that normal diurnal increases in plasma cortisol, independent of the content of the morning meal, contribute to the increased amount of morning insulin required in diabetic subjects. Programs designed for optimal open loop insulin delivery may benefit from modifications designed to coincide with this increase in amount of basal insulin required in the early morning.

Influence of growth hormone on overnight insulin requirements in insulin-dependent diabetes.

After a 0100-0300 h nadir, the insulin requirements to maintain blood glucose at 90-110 mg/dl increase substantially in the prebreakfast (0600-0800 h) period in some insulin-dependent diabetic patients (IDDMs). Early insulin-like and delayed insulin-antagonistic effects of physiologic early morning increases in growth hormone (hGH) secretion may account for this variability of overnight insulin requirements. To assess the role of hGH, we studied five IDDMs using a closed-loop insulin infusion device (Biostator, GCIIS). Either saline (C) or somatostatin plus glucagon (SRIF + G) was infused during separate overnight (2400-0800 h) study periods. An infusion of hGH from 2400 to 0130 h was added to SRIF + G infusion during an additional study period (SRIF + G + hGH). In comparison to 0100-0300 h, mean insulin infusion rates required to maintain blood glucose values between 105 and 120 mg/dl during the prebreakfast period increased by 66 +/- 25% during C, and 42 +/- 12% during SRIF + G when serum growth hormone was suppressed to less than or equal to 0.75 ng/ml. During SRIF + G + hGH, the mean prebreakfast insulin infusion rate increased by 42 +/- 11% with a mean peak hGH level of 14.7 +/- 5.4 ng/ml at 0130 h. Mean plasma free insulin levels remained constant during the night despite the significantly higher insulin infusion rates between 0600 and 0800 h. During SRIF + G, insulin requirements remained constant overnight before 0600 h, whereas during both C and SRIF + G + hGH conditions, a nadir was noted between 0100 and 0300 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative roles of insulin clearance and insulin sensitivity in the prebreakfast increase in insulin requirements in insulin-dependent diabetic patients.

During continuous subcutaneous or intravenous insulin infusion therapy, many patients with insulin-dependent diabetes (IDD) require more insulin in the prebreakfast period (0600-0800 h) than earlier in the morning (0100-0300 h). This study was designed to assess whether variations in insulin clearance or insulin sensitivity might contribute to overnight variations in insulin requirements. Euglycemic insulin clamp studies were performed in random sequence from 2400 to 0300 h and from 0500 to 0800 h on successive nights in 10 subjects with IDD. Insulin was infused at a rate of 40 mU/min/m2 and plasma glucose concentration was maintained at 100 mg/dl by a variable rate glucose infusion from a Biostator GCIIS (Miles Laboratories, Elkhart, Indiana). Insulin clearance was (mean +/- SEM) 277 +/- 41 ml/min/m2 between 0700 and 0800 h compared with 256 +/- 41 ml/min/m2 between 0200 and 0300 h (P less than 0.05), while glucose infusion rates were the same [3.86 +/- 0.52 mg/kg/min from 0730 to 0800 h versus 3.99 +/- 0.51 mg/kg/min from 0230 to 0300 h (P = NS)]. All eight patients with a previously documented prebreakfast increase in insulin requirements had higher insulin clearance at this time. These results indicate that differences in insulin clearance between the prebreakfast period and the early morning may account partially for the higher prebreakfast insulin requirements in some subjects with IDD, and the variations in insulin requirements during the night are not due to variations in insulin sensitivity.

Reversal of abnormalities in ocular fluorophotometry in insulin-dependent diabetes after five to nine months of improved metabolic control.

Abnormalities in ocular fluorophotometry occur in human and experimental diabetes mellitus. To determine the reversibility of these abnormalities, we studied prospectively 11 intensively treated and 25 conventionally treated insulin-dependent diabetics (IDD) preselected because of abnormal vitreous fluorophotometry. Among the 25 IDD treated conventionally with one or two insulin injections daily, hemoglobin A1C concentrations remained elevated and fluorescein concentration, 1 h after the intravenous injection of fluorescein (7 mg/kg), did not change significantly in either the anterior chamber or the posterior vitreous. Among 11 IDD treated intensively with home blood glucose monitoring and pumped subcutaneous insulin or three or more injections daily, hemoglobin A1C fell dramatically (10.4 +/- 0.7% to 7.5 +/- 0.2%) and anterior chamber fluorescein concentration decreased (73.9 +/- 7.7 to 49.5 +/- 5.3 ng/ml). Two patients with proliferative retinopathy showed no improvement in their massive vitreous fluorescein accumulation and subsequently required photocoagulation. In the nine subjects without proliferative retinopathy, vitreous fluorescein accumulation decreased in eight (10.6 +/- 0.7 to 6.5 +/- 0.5 ng/ml) and was normal in six after 1 yr. The only subject with increasing vitreous fluorescein accumulation also had concurrent worsening of background retinopathy. These studies support the hypothesis that moderate abnormalities in ocular fluorophotometry are due to reversible changes in ocular tissues, such as retinal pigment epithelium. Fluorescein leakage emanating from the advanced vascular or retinal abnormalities of proliferative retinopathy were not reversed with the degree and duration of metabolic control achieved in the present study. The long-term significance of the reversal of moderate abnormalities in fluorophotometry is not clear at the present time.

Insulin clearance contributes to the variability of nocturnal insulin requirement in insulin-dependent diabetes mellitus.

We have previously described, in insulin-dependent diabetic subjects (IDDM), a small, but significant, increase in the insulin clearance rate (ICR) during 0600-0800 h as compared with 0100-0300 h. To determine whether this increase was also seen at more physiologic levels of insulin replacement, we calculated ICR during euglycemic clamp studies in 13 patients with IDDM with a constant infusion of insulin at 20 mU/min/m2 and during insulin replacement from the Biostator GCIIS without exogenous glucose. During the euglycemic clamp study with constant insulin infusion at 20 mU/min/m2, the ICR was 16% higher at 0600-0800 h than at 0100-0300 h (264 +/- 50 ml/min/m2 versus 228 +/- 51 ml/min/m2; P less than 0.005). During insulin replacement by the Biostator, the mean insulin infusion rate increased by 92 +/- 27% (7.5 +/- 1.1 to 13.5 +/- 1.2 mU/min/m2; P less than 0.001) and ICR increased by 123 +/- 30% (130 +/- 24 to 268 +/- 51 ml/min/m2; P less than 0.01) during the prebreakfast period when compared with 0100-0300 h. There was a highly significant correlation (r = 0.97) between the increment in insulin infusion rate and the increment in ICR. Measurement of insulin concentration in saline solutions, delivered by the Biostator at a same rate and under similar conditions to those in this study, showed that insulin delivery was stable for the 8-h period of this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose counterregulation in pre-school-age diabetic children with recurrent hypoglycemia during conventional treatment.

To determine whether immature or defective glucose counterregulation was responsible for the severe recurrent hypoglycemic episodes (3.6 per patient per year) observed during conventional therapy (CT) in six pre-school-age diabetic children, we investigated their metabolic and hormonal responses to insulin infusion (40 mU/kg i.v. for 60 min). Counterregulation was considered adequate because no patient experienced symptoms requiring discontinuation of the test, and blood glucose (BG) nadirs averaged 42 +/- 5 mg/dl. Glucose production rate decreased from 4.2 +/- 0.2 to 2.6 +/- 0.6 mg X kg-1 X min-1. Blood 3-hydroxybutyrate levels were elevated (approximately 3 mM) and did not change during insulin infusion. The responses of epinephrine (from 137 +/- 37 to 393 +/- 143 pg/ml), norepinephrine (from 145 +/- 33 to 347 +/- 152 pg/ml), and growth hormone (from 6.0 +/- 1.5 to 20.3 +/- 5.1 ng/ml) were normal for this age group. As previously observed in diabetic adults, glucagon response was deficient (from 117 +/- 30 to 114 +/- 18 pg/ml). The six children were subsequently treated with continuous subcutaneous insulin infusion (CSII), which resulted in a 20-fold decrease in the number of severe hypoglycemic reactions. Predisposition to severe hypoglycemia in this subset of diabetic children, which remains a refractory problem even after considerable efforts have been made to decrease them, may thus be sharply decreased with CSII therapy. During this therapy, a significant inverse correlation appeared between the individual frequency of BG values less than 40 mg/dl and BG nadir during the insulin infusion test (r = .94, P less than .001).

Examination of the role of the pituitary-adrenocortical axis, counterregulatory hormones, and insulin clearance in variable nocturnal insulin requirements in insulin-dependent diabetes.

In insulin-dependent diabetics, insulin requirements increase significantly after 0600 h, resulting in prebreakfast hyperglycemia with either conventional insulin therapy or constant insulin infusions with insulin infusion devices. In order to clarify the role of the pituitary-adrenocortical axis and further examine the mechanisms of the phenomenon of nocturnal variability in insulin requirements, we studied five IDDs using a closed-loop insulin infusion device (Biostator, GCIIS). The subjects were given saline (SAL) or dexamethasone (DEX) i.v. from 1800 to 0900 h on successive nights. From 2400-0300 to 0600-0900 h, mean insulin infusion rates required to maintain blood glucose values between 109 and 120 mg/dl increased by 0.21 +/- 0.05 mU/kg/min during the SAL infusion, and 0.16 +/- 0.04 mU/kg/min during the DEX infusion, when plasma cortisols were suppressed to less than or equal to 2 micrograms/dl. Mean free insulin concentrations did not increase and remained constant throughout both study nights in spite of the significantly higher 0600-0900-h insulin infusion rates. Growth hormone, glucagon, epinephrine, and norepinephrine concentrations showed normal nocturnal and early morning patterns during both study nights. We conclude that the nocturnal variability in insulin requirements persists despite suppression of the pituitary-adrenocortical axis, and that increased free insulin clearance or degradation may contribute to the "dawn phenomenon" of rising prebreakfast glucose despite constant insulin infusion.

Plasma pancreatic polypeptide response to insulin-induced hypoglycemia as a marker for defective glucose counterregulation in insulin-dependent diabetes mellitus.

Defective glucose counterregulation occurs in some insulin-dependent diabetic subjects (IDDMs) as a result of a combined deficiency of glucagon (IRG) and epinephrine (EPI) secretion in response to insulin-induced hypoglycemia. To determine whether the deficient glucagon response, the deficient epinephrine response, or both are manifestations of autonomic dysfunction, we used the pancreatic polypeptide (PP) secretory response to insulin-induced hypoglycemia as a marker for autonomic neuropathy. Seven nondiabetic controls and 21 IDDMs were given insulin at 40 mU/kg/h after overnight euglycemia. Eight of the IDDMs had defective counterregulation (-CR), and 13 had adequate counterregulation (+CR) by our previously published criteria. Those with -CR had a blunted EPI (delta EPI = 102 +/- 16 pg/ml; mean +/- SEM) and PP (delta PP = 12 +/- 13 pg/ml) response as compared with controls (delta EPI = 310 +/- 49; delta PP = 498 +/- 43) and IDDMs with +CR (delta EPI = 291 +/- 32; delta PP = 521 +/- 86). In controls, IRG rose by 31 +/- 6 pg/ml; in IDDMs, IRG failed to rise significantly above baseline regardless of counterregulatory status. Although the PP and EPI responses correlated well (r = 0.626, P less than 0.001), the IRG response failed to correlate with either the EPI or the PP response. We conclude that the deficient epinephrine, but not glucagon, secretory response to hypoglycemia in diabetic subjects is a result of autonomic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential autoantigens in IDDM. Expression of carboxypeptidase-H and insulin but not glutamate decarboxylase on the beta-cell surface.

Insulin, carboxypeptidase-H (CP-H), and glutamate decarboxylase (GAD) have been identified as potential autoantigens in insulin-dependent diabetes mellitus (IDDM). Previous studies have described immunoreactive insulin as a surface molecule on the plasma membrane of rat islet cells and suggested that cell-surface insulin was derived during exocytosis by the fusion of insulin secretory granules with the beta-cell plasma membrane. These findings predict that insulin and other secretory granule-derived proteins such as the putative autoantigen CP-H may be colocalized with insulin at specific sites of exocytosis on the beta-cell surface. In studies to test this hypothesis, cell-surface staining of dispersed rat islet cells occurred in a granule-like pattern with antibodies for CP-H and insulin. The specificity of the CP-H antiserum was confirmed by immunoblotting and indicated that the antiserum was essentially monospecific for CP-H. Confocal laser microscopy confirmed that immunoreactive staining for CP-H and insulin was confined to the beta-cell surface. Colocalization of CP-H and insulin on the cell surface of beta-cells was demonstrated by double staining with antibodies to CP-H and insulin, and the percentage of beta-cells positive for both of these autoantigens increased twofold with increases in insulin secretion. In contrast, islet cells failed to reveal cell-surface staining for GAD65, another putative autoantigen in IDDM, under either basal or insulin stimulatory conditions or following exposure of islet cells to the cytokines interleukin-1 beta, tumor necrosis factor-alpha, and recombinant human interferon-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin independence after islet transplantation into type I diabetic patient.

Effective clinical trials of islet transplantation have been limited by the inability to transplant enough viable human islets into patients with type I (insulin-dependent) diabetes mellitus to eliminate their exogenous insulin requirement. We report the first type I diabetic patient with an established kidney transplant on basal cyclosporin immunosuppression who was able to eliminate the insulin requirement after human islet transplantation into the portal vein. We successfully isolated approximately 800,000 islets that were 95% pure from 1.4 cadaver pancreases containing 121 U of insulin. Islets were proven viable by in vitro insulin response to glucose challenge. After 7 days of 24 degrees C culture, the islets were transplanted into the portal vein under local anesthesia. Seven days of Minnesota antilymphoblast globulin (20 mg/kg) administration followed the islet transplantation, with maintenance of the cyclosporin. Blood glucose was kept under strict control via intravenous insulin for 10 days posttransplantation, when all insulin therapy was stopped. Off insulin, the average 24-h blood glucose level remained less than 150 mg/dl, with the fasting glucose level at 115 +/- 6 mg/dl and the 2-h postprandial level at 141 +/- 8 mg/dl for 22 days posttransplantation (the time of this study). The C-peptide values post-Sustacal testing, although initially rising slower, exceeded the normal range, with peak values of 1.0-1.8 pmol/ml. This preliminary result represents the first essential step required to determine the feasibility of islet transplantation by future clinical trials.

Abnormal myocardial acoustic properties in diabetic patients and their correlation with the severity of disease.

Although patients with diabetes mellitus may be afflicted by cardiomyopathy, its prevalence and nature are controversial. Studies have shown that fibrosis alters the acoustic properties of the heart in animals and humans and that the changes are detectable by cardiac tissue characterization with ultrasound. The present study was performed to characterize myocardial acoustic properties in patients with insulin-dependent diabetes to determine whether ultrasound tissue characterization could detect changes potentially indicative of occult cardiomyopathy. The magnitude of cyclic variation of myocardial ultrasound integrated backscatter and its phase delay with respect to the onset of the cardiac cycle in the septum and posterior wall of the left ventricle were measured in 54 patients with diabetes who had no overt cardiac disease. Conventional echocardiography documented normal ventricular systolic function in 96%. As compared with results in age-matched patients without diabetes studied previously, cyclic variation of integrated backscatter was reduced (4.6 +/- 0.8 vs. 3.6 +/- 1.4 dB; p less than 0.001). In addition, delay was significantly increased (0.86 +/- 0.09 vs. 0.99 +/- 0.15). The primary analysis of the data focused on differences among the diabetic patients. Reduction of cyclic variation of backscatter was greatest in patients with diabetes who had neuropathy (3.2 +/- 1.0 dB; p less than 0.001) as was the increase in delay (1.04 +/- 0.16, p less than 0.001 vs. values in patients without neuropathy). Retinopathy and nephropathy were associated with abnormal myocardial acoustic properties as well. Thus, abnormalities that may reflect fibrosis or other occult cardiomyopathic changes in diabetic patients without overt heart disease are readily detectable by myocardial tissue characterization with ultrasound and parallel the severity of noncardiac diabetic complications.

Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions.

At least 90% of the 12 to 15 million persons with diabetes mellitus in the United States, half of whose condition remains undiagnosed, have type 2 diabetes. Type 2 diabetes is preceded by a long period of impaired glucose tolerance, a reversible metabolic state associated with increased prevalence of macrovascular complications. Thus, at the time of diagnosis, long-term complications have developed in almost one fourth of patients. Susceptibility to type 2 diabetes requires genetic (most likely polygenic) and acquired factors, and its pathogenesis involves an interplay of progressive insulin resistance and beta-cell failure. The ideal treatment of type 2 diabetes should reverse insulin resistance and beta-cell dysfunction in most treated patients and prevent, delay, or reverse long-term complications. Current strategies are aimed at amelioration of insulin resistance (diet, exercise, weight loss, and metformin and troglitazone therapy), augmentation of insulin supply (sulfonylurea and insulin therapy), or limitation of postprandial hyperglycemia (acarbose therapy). Future therapies probably will target (1) insulin resistance, using a multifaceted approach; (2) hepatic glucose production, using gluconeogenesis inhibitors; (3) excess nonesterified fatty acid production, using lipolysis inhibitors; and (4) fat oxidation, using carnitine palmitoyltransferase I and II inhibitors. Attempts also could be made to stimulate energy expenditure and increase nonoxidative glucose disposal by means of beta 3-adrenoceptor agonists. One promising strategy is an attack on multiple pathophysiological processes by combining antidiabetic agents with disparate mechanisms of action. Thus, we now have unprecedented resources for drug therapy for diabetes, with great opportunity for innovative combinations. It is hoped that these expanded choices will provide the tools necessary for a more efficient management of type 2 diabetes and prevention of its long-term complications.

Retinopathy in African Americans and whites with insulin-dependent diabetes mellitus.

BACKGROUND: The development and progression of diabetic retinopathy in African Americans with insulin-dependent diabetes mellitus is not known. METHODS: Two hundred subjects with insulin-dependent diabetes mellitus with duration of diabetes 16 years or less at first visit were studied; 58 were African Americans and 142 were whites. All had gradable stereoscopic color fundus photographs (seven standard fields) from at least two visits (mean time between first and second visit was 4.1 years). Subjects with hemoglobinopathy or proliferative retinopathy or subjects who had evidence of treatment for proliferative retinopathy at first visit were excluded. Masked grading of photographs was conducted using the modified Airlie House classification scheme. RESULTS: African Americans were older, heavier, had higher systolic blood pressure (all P < .05), and marginally higher hemoglobin A1 (HbA1) values (P = .06) than the whites at first visit. African Americans had a lower rate of two steps or more progression from preexistent retinopathy (19%) than whites (43%). Progression to proliferative retinopathy or treatment was similar by race. Multivariate analysis predicting development oe progression of retinopathy, while controlling for length of follow-up, found higher HbA1 (odds ratio [OR] = 2.15), longer duration of insulin-dependent diabetes mellitus (OR = 1.69), higher serum creatinine concentration (OR = 1.59), and white race (OR = 2.62) to be independent risk factors. CONCLUSIONS: These data suggest a previously unsuspected reduction in the adjusted risk for development and progression of retinopathy in African Americans. The reason for this apparently reduced risk are not known.

Localized skin reactions to insulin: insulin lipodystrophies and skin reactions to pumped subcutaneous insulin therapy.

Patients treated with insulin can develop a variety of adverse cutaneous and subcutaneous reactions localized at sites of insulin injection. The reported frequency, severity, and type of skin reactions to insulin are varied, as are the theories relating to their etiology and recommendations for treatment. In this review, several types of localized skin reactions to insulin injection will be described. Particular attention will be devoted to insulin lipoatrophy and skin reactions in patients using mechanical devices for continuous subcutaneous insulin infusion. Recent advances in diabetes care have made insulin-induced lipoatrophy a preventable and treatable disorder. However, localized skin reactions are emerging as a potential problem among users of insulin infusion pumps.

Development of proliferative diabetic retinopathy in African-Americans and whites with type 1 diabetes.

OBJECTIVE: To investigate the comparable risk of developing proliferative diabetic retinopathy (PDR) in African-Americans and whites with type 1 diabetes. RESEARCH DESIGN AND METHODS: Using a cohort design with the sample drawn from medical records, the sample consisted of 312 people with type 1 diabetes (97 African-Americans, 215 whites) having at least two visits to a Model Demonstration Unit with gradeable fundus photographs (stereo, color, 7 standard fields). Excluded were subjects with preexisting or treated PDR or hemoglobinopathy. Masked grading of the fundus photographs was conducted at the Wisconsin Reading Center. RESULTS: At baseline, African-Americans had poorer glycemic control (mean HbA1 of 11.3 vs. 10.0%, P < 0.0001), higher systolic blood pressure (mean of 117 vs. 110 mmHg, P < 0.001), and were older (mean of 26.8 vs. 19.3 years, P < 0.0001) than the white subjects. African-Americans also tended to have slightly longer duration of diabetes and length of follow-up. In the African-Americans, 17.5% developed PDR, compared with 10.2% in the 215 whites, for an odds ratio (OR) of 1.86 (95% CI 0.93-3.70). When adjusted for baseline glycemic control, retinopathy grade, and length of follow-up, race was not a significant risk factor (OR = 0.73, 95% CI 0.30-1.78). CONCLUSIONS: African-Americans with type 1 diabetes may have a higher rate of developing PDR. The observed racial difference, however, is attributable to the presence of a worse risk factor profile, especially to poorer glycemic control. Efforts should be expanded to improve the care for all individuals with poor glycemic control.

Disparity in glycemic control and adherence between African-American and Caucasian youths with diabetes. Family and community contexts.

OBJECTIVE: To describe sociodemographic, family, and community factors that contribute to the glycemic control of African-American and Caucasian youths with diabetes, we investigated two questions: 1) Is there a disparity in glycemic control between African-American and Caucasian youths with diabetes, and if so, what sociodemographic, family, and community factors explain the disparity? and 2) Is there a difference in the adherence to treatment between African-American and Caucasian youths with diabetes, and if so, what sociodemographic, family, and community factors explain the difference? RESEARCH DESIGN AND METHODS: This cross-sectional study included 146 youths with diabetes (95 Caucasians and 51 African-Americans) and their mothers. The youths were invited to participate if they had been diagnosed with diabetes at least 1 year before the study, did not have another chronic illness, and were < 18 years of age. RESULTS: The findings indicate that African-American youths with diabetes are in significantly poorer metabolic control than their Caucasian counterparts (1.5% difference in HbA1c levels). Single-parent household status and lower levels of adherence partially account for the poorer glycemic control. Examination of the adherence subscales indicates that African-Americans report significantly lower adherence to diet and glucose testing than Caucasian youths. CONCLUSIONS: This study suggests that African-American youths with diabetes may be at greater risk for poor glycemic control due to the higher prevalence of single parenting and lower levels of adherence found in this population.